5-HTP and Trp, which are precursors of serotonin, represent a significant approach in the treatment of conditions that involve serotonin synthesis and release in the CNS. The main interest in the use of Trp and its metabolites derives from the fact that they represent a natural alternatives to traditional antidepressants, such as for example, the selective serotonin reuptake inhibitors (SSRI), and minor long-term adverse effects are expected when using 5-HTP and Trp. Among the pathologies or conditions associated with serotonin deficiency in the Nervous System are the mood disturbances, the depression, the fibromylagia syndrome, the serotonin-dependent headache, the overweight and the obesity. The use of a direct supplementation with serotonin is not applicable because serotonin does not cross the blood-brain barrier (BBB). Trp is transported across the BBB by means of a carrier mechanism, while 5-HTP crosses easily the BBB.
The synthesis of serotonin, both centrally and peripherally, starts with hydroxylation of Trp to 5-HTP by means of 5-tryptophan-hydorxylase, the rate-limiting enzyme in the serotonin synthesis, as other compounds, like proteins, niacin or kynurenines are also synthesized from Trp. 5-HTP is subsequently converted to serotonin by an aromatic amino acid decarboxylase (MAD) that depends on pyridoxine as coenzyme. It has been well documented (J H Juhl, “Fibromylagia and the Serotonin Pathway”, Altern Med Rev 1998; 3 5 L. 365-375) that the amount of Trp transformed in serotonin is between 2 to 10% of the total Trp present. Excess Trp induces the enzyme pyrrolase and thus deviates Trp metabolism in the direction of the kynurenine pathway leading to the synthesis of niacin, kynurenines and picolinic acid (I. P. Lapin, Epilepsia, 22:257 1981).
Because of those peculiarities in the serotonin synthesis, it is essential that Trp should be administered in quantities that would prevent overloading the serotonin-conversion pathway, thus avoiding that the corresponding substrates (in the case Trp and 5-HTP) are utilized in an inefficient manner for synthesis of serotonin, therefore leading to undesirable metabolic outcome. Maintaining bioavailable Trp levels for longer periods of time would allow for a better therapeutic efficacy with lower dosages, overcoming the appearance of potential side effects caused by acute administration of elevated quantities of Trp or 5-HTP. Considering that the rate-limiting step in the serotonin synthesis is the conversion of Trp to 5-HTP, the specific metabolic requirements would be those that hamper a massive release of Trp in the gastrointestinal tract, as it is known that high concentrations of 5-HTP provoke side-effects such as nausea and/or epigastric burning.
On the other hand, in order to obtain a rapid and efficient therapeutic response it is essential to supply promptly an adequate quantity a serotonin precursor, without overloading the enzymatic conversion steps. The currently available formulations do not take into consideration the peculiarities of the serotonin synthesis and actually no formulations containing 5-HTP and Trp that satisfy the metabolic requirements of the organism are available.